Abstract

Background

Pro-dopaminergic pharmacological interventions have shown promise in treating anhedonia in people with depression, prompting us to conduct a living systematic review to synthesise data from human and non-human studies.

Methods

We co-produced a living systematic review of controlled studies investigating the efficacy of pro-dopaminergic interventions in reducing symptoms of anhedonia in people with depression and relevant animal models. Multiple electronic databases were searched, from which studies were screened, extracted and assessed for risk of bias by two independent reviewers (until 09.11.2023). The primary outcomes were standardised mean differences (SMD) for anhedonia symptoms in human studies and sucrose preference test for animal models. We synthesised data with random-effects meta-analyses and calculated prediction intervals to better report the effects of heterogeneity. We also analysed drop-out rates and occurrences of specific adverse events. To contextualise the results of pro-dopaminergic drugs, we performed a series of random effects network meta-analyses on a specific anhedonia item also from other antidepressant agents.

Results

We included 6 human studies and found that pro-dopaminergic interventions were better than placebo in reducing symptoms of anhedonia (n= 2076; SMD -0.24, 95%CI -0.46 to -0.03). Eleven studies in people with depression reported data about anxiety and pro-dopaminergic interventions were more efficacious in reducing symptoms compared to placebo (n= 3517, SMD -0.17, 95% CI -0.24 to -0.09). We did not find data in human studies about reward and reinforcement. In animal models, pro-dopaminergic interventions improved sucrose preference (27 studies, SMD 1.34, 95% CI 0.88 to 1.79) and we found evidence that the mechanism of pro-dopaminergic interventions occurred via an indirect pathway, highlighting the role of dopamine metabolism. Additional analysis of human data found that other non-dopaminergic antidepressants (e.g., some selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) showed greater improvements in anhedonia symptoms compared to bupropion, the pro-dopaminergic antidepressant included in the analysis.

Conclusion

Pro-dopaminergic interventions are more effective at reducing anhedonia in humans than placebo and in animal models of depression; this supports the existing evidence on the role of dopamine in reward systems. However, this may occur via an indirect pathway and at the moment it is not possible to distinguish between a specific effect of pro-dopaminergic interventions on anhedonia and a more general effect of antidepressants on these symptoms. More data on reward and reinforcement in humans with anhedonia are needed to better triangulate human and animal evidence sources and properly examine the relationship between dopamine modulation and anhedonia.

Plain language summary

Anhedonia is a common feature of depression, where a person lacks general interest, motivation, and enjoyment. It is thought that a lack of dopamine is associated with symptoms of anhedonia in people with depression. Some studies found that pro-dopaminergic drugs, which are drugs that can mimic the effects of dopamine in the brain, can reduce symptoms of anhedonia. However, it is unknown how these drug treatments can target the processes in our body that cause anhedonia.

The goal of this project was to review information from published studies on how pro-dopaminergic drugs (medications such as certain antidepressants or stimulants) target processes in the body that cause anhedonia. As this is a living systematic review, the team will search for new studies every 3 months and this report will be updated when new evidence is available.

We found that pro-dopaminergic drugs reduced anhedonia and decreased anxiety in human studies. These studies also mentioned that the dopamine agents were tolerated well, however, many participants discontinued the treatment due to side effects. Similarly, we found that pro-dopaminergic agents increased dopamine levels in animals.

Further research is needed to better understand the role of pro-dopaminergic agents in reducing anhedonia, specifically on reward and reinforcement tasks which will help us examine the mechanism underlying anhedonia in more detail. Future work should explore how the different mechanisms of these drugs affect symptoms of anhedonia, as well as adding other drugs to a patient’s treatment in addition to the pro-dopamine agent. Future studies should also include a range of pro-dopaminergic drugs as currently the majority of studies measuring anhedonia used one antidepressant. This would allow us to be more confident in the effects of dopamine rather than the one antidepressant.

1. Methods (brief)

In this first iteration of the living systematic review we searched for randomised controlled trials that compared pro-dopaminergic interventions to placebo in adults with unipolar depression (i.e. above-threshold symptoms on any standardised measure, or a clinical diagnosis based on any operationalised criteria).

Eight databases were searched from inception up to the 9th of November, 2023 (see protocol for full search strings). Database search results were imported into EPPI-Reviewer and duplicates were removed prior to screening. All steps related to record screening and data extraction were completed in EPPI-Reviewer.

Titles and abstracts of the identified records were screened by at least two reviewers (CF, MC, JK, JP). We retrieved the full-texts and any supporting documents for all records that were not excluded at the title and abstract screening stage. The full-text screening was conducted by at least two reviewers (CF, JK, JP, AK, EB). Conflicts at title and abstract, and full-text screening, were resolved through discussion between the two reviewers and involvement of a third reviewer (AC, EGO).

We focused on the following outcomes: - anhedonia symptom severity: using anhedonia-specific scales, anhedonia-specific sub-scales, or individual items focusing on anhedonia (observer-rated or self-rated). Continuous, primary outcome. - anxiety symptom severity: as per observer or self-reported standardised scales. Continuous, secondary outcome. - acceptability: proportion of participants dropping out for any reason. Binary, secondary outcome. - tolerability: the proportion of participants dropping out due to an adverse event. Binary, secondary outcome. - safety: the proportion of participants reporting specific adverse events (nausea, headache, insomnia, constipation, dizziness, dry mouth, vomiting). Binary, secondary outcome.

Additional information on the full study eligibility criteria can be found in the pre-published protocol.

For anhedonia and anxiety symptom severity, we extracted outcome data reported at 8 weeks post-treatment or manipulation. If the information at 8 weeks was not available, we considered eligible data ranging between 4 and 12 weeks (with preference to the time point closest to 8 weeks and, if equidistant, the longer outcome). For acceptability, tolerability, safety and safety (specific adverse events), we extracted outcome data reported at the end of the studies.

When extracting continuous outcomes we extracted mean and standard deviation to two decimal places. Where standard error was reported, we converted the value to standard deviation. Baseline and endpoint values were extracted. These were preferred to change in score and endpoint, in which case the missing value was calculated by adding or subtracting the change in score from the time point given.

When extracting dichotomous outcomes we extracted natural numbers and where only percentages of participant groups were reported, a value was calculated and rounded up to the nearest natural number. Adverse events were extracted using the exact wording used to report them in the included studies.

Relevant data was extracted using EPPI-Reviewer by at least two reviewers (CF, CA, EB, JK). EPPI-Reviewer was used to screen records, extract data, and assess risk of bias.

We assessed risk of bias with the RoB2 tool (Higgins et al. 2019). All outcomes for all included studies were assessed by at least two reviewers (JK, CF, CA, AH) and conflicts were resolved by discussion between reviewers. To evaluate biases due to missing evidence, the ROB-ME tool (Page et al. 2023) was used with the same double screening and conflict resolution process as described above.

Effect sizes were calculated as standardised mean differences (SMDs) for continuous outcomes (anhedonia and anxiety symptom severity) and odds ratios (ORs) for dichotomous outcomes (acceptability, tolerability, and specific-adverse events). We calculated the 95% confidence interval (CI) around the pooled effect size for each meta-analysis.

Meta-analyses were conducted using a random effects model with the inverse variance method, using the restricted maximum-likelihood estimator for 𝞽2 and the Hartung-Knapp correction method to adjust 95% confidence intervals, if there are at least five studies. Prediction intervals of the overall pooled effect were calculated to convey the amount of heterogeneity.

In order to better contextualise pro-dopaminergic interventions within wider literature on the effects of antidepressants on anhedonia, we aggregated individual participant data (IPD) on the MADRS “inability to feel” item from 34 randomised controlled trials (14054 participants) on antidepressants in people with depression that we had access to. We utilised this post-hoc analysis to add further evidence on the impact of non-dopaminergic intervantions on anhedonia in depression and in doing so, better understand the evidence we analysed on dopamine-specific drugs. We performed the following analyses to estimate the performance of bupropion versus placebo at the primary outcome (i.e. reduction in anhedonia scores):

Meta-regressions were planned for the following variables: mean age of participants, mean anhedonia baseline score, mean anxiety baseline score, sex (proportion of female participants), and planned treatment duration. Meta-regressions were only conducted for outcomes where data was available from 10 or more studies.

Summary of evidence tables were constructed for all outcomes including a summary of the meta-analytic result, biases within-study, across-study, and due to indirectness.

Please refer to the protocol and the extended data for more details.

A list of abbreviations can be found towards the end of the document.

2. Results

2.1 Flow diagram

Figure 1. PRISMA 2020 flow diagram. ` Table 1. Characteristics of included studies that reported anhedonia scores. NA = not available.

2.2 Description of included studies

We identified 63 eligible studies. The characteristics of the identified studies can be found in Table 1. Data from studies contributed with at least one outcome with quantitative data (total of 10532 participants), which included adults from multiple countries. The mean age of participants was 42.2 years (range 15 to 72 years), with a mean proportion of 0.58 female participants (range 0 to 0.86). Included studies allocated the participants to treatment lasting between 4 to 12.9 weeks (median, 6 weeks).

2.3 Primary outcome: reduction in anhedonia scores at 8 weeks (from 4 to 12 weeks)

2.3.1 Pairwise meta-analysis

Figure 2. Forest plot for symptoms of anhedonia (primary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anhedonia at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95% CI: 95% confidence intervals, SD: standard deviation.

The effect of pro-dopaminergic drugs versus placebo showed an effect favouring pro-dopaminergic interventions with a SMD of -0.244 (95% CI from -0.456 to -0.031). There is some heterogeneity as shown by the 95% prediction interval from -0.74 to 0.252.

2.3.2 Risk of bias

Figure 3. Risk of bias assessment.

Evidence for the efficacy of pro-dopaminergic interventions vs placebo were rated as having a range in their overall risk of bias. Two studies (33%) were assessed as having ‘high’ risk of bias due to having ‘high’ risk of bias in the missing outcome data domain and selection of the reported results domain. Two studies (33%) had an overall ‘moderate’ risk of bias rating as they had ‘some concerns’ in two domain ratings. The remaining two studies were rated as having a ‘low’ overall risk of bias.

2.3.3 Reporting bias

The extent to which the result was affected by reporting biases was rated as low as per the RoB-ME assessment (Page et al. 2023). This was as the potential for missing studies across the review was judged to be low. In addition, none of the included studies were deemed to have generated an eligible result that was not reported, and no studies were judged to be unclear as to whether they generated an eligible result that was not reported. We made this decision based on the results matrix we generated in step 2 of the RoB-ME tool (Page et al. 2023).

2.3.4 Meta-regression analyses

We did not perform any meta-regressions as the total number of studies was below 10.

2.3.5 Post-hoc analyses

We had access to individual participant data (IPD) of randomised controlled trials on depression from a NIHR-funded project. We performed a series of post-hoc analyses on the MADRS “inability to feel” item (aggregated IPD from 34 studies, 14054 participants).

We conducted network meta-analysis. Figure 4 shows the results of each active drug versus placebo. SMD: standardised mean difference, 95% CI: 95% confidence intervals, SD: standard deviation.

Figure 5. Summary SMD for the ‘inability to feel’ item on the MADRS scale, from indirect and direct evidence (network meta-analysis) of antidepressant versus placebo. Buproprion is the only pro-dopaminergic drug shown.

The mean effect of bupropion (pro-dopaminergic intervention) versus placebo was -0.12 (SMD, 95% CI from -0.25 to 0.00; 34 studies, 14054 participants). In comparison, we found effects across non-dopaminergic interventions to range from -0.09 (SMD, 95% CI from -0.19 to 0.08) in agomelatine to -0.50 (SMD, 95% CI from -0.48 to -0.32) in duloxetine. The range of effects found for bupropion verses non-dopaminergic interventions was 0.28 (SMD, 95%CI from -0.15 to 0.41) to -0.07 (SMD, 95%CI from -0.23 to 0.09).

2.4 Secondary outcome: Reduction in mean anxiety score at 8 weeks (from 4 to 12 weeks)

2.4.1 Pairwise meta-analysis

Figure 6 Forest plot for symptoms of anxiety (secondary outcome) comparing pro-dopaminergic interventions vs placebo for individuals with anxiety at 4-12 weeks (primary timepoint). SMD: standardised mean difference, 95% CI: 95% confidence intervals, SD: standard deviation. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.4.2 Risk of Bias

Figure 7. Risk of bias assessment.

2.4.3 Meta-regression analyses

The table below shows which of the covariates could modify the treatment effect of pro-dopaminergic interventions on anxiety symptom severity.

SMD 95% CI 𝞽2
Unadjusted effect -0.166 -0.243 to -0.088 0
Moderator 95% CI 𝞽2
Anxiety baseline (per point increase) 0.01 -0.01 to 0.03 0
Age (per 10 year increase) 0 -0.06 to 0.06 0
Female proportion (per percentage point increase) -0.15 -1.85 to 1.55 0
Treatment duration (per week increase) 0.01 -0.05 to 0.08 0

2.5 Secondary outcome: Dropouts due to any reason

2.5.1 Pairwise meta-analysis

Figure 8 Forest plot for dropouts due to any reason for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals.RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.5.2 Risk of bias

2.5.3 Meta-regression analyses

Figure 9. Risk of bias assessment.

The table below shows which of the covariates, if any, explain some of the heterogeneity (𝞽2) observed in the effect sizes of the effect of pro-dopaminergic interventions on acceptability.

OR 95% CI 𝞽2
Unadjusted effect 0.965 0.794 to 1.172 0.22
Moderator 95% CI 𝞽2
Anxiety baseline (per point increase) 1.03 0.99 to 1.07 0.01
Age (per 10 year increase) 0.88 0.71 to 1.09 0.24
Female proportion (per percentage point increase) 0.44 0.09 to 2.13 0.22
Treatment duration (per week increase) 0.99 0.9 to 1.1 0.25

The smaller 𝞽2 value for anxiety baseline suggests that this variable seem to explain the heterogeneity.

2.6 Secondary outcome: dropouts due to side effects

2.6.1 Pairwise meta-analysis

Figure 10 Forest plot for dropouts due to adverse events for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals.RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.6.2 Risk of bias

Figure 11. Risk of bias assessment.

2.6.3 Meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity (𝞽2) observed in the effect sizes of the effect of pro-dopaminergic interventions on tolerability.

OR 95% CI 𝞽2
Unadjusted effect 1.825 1.382 to 2.41 0.23
Moderator 95% CI 𝞽2
Anxiety baseline (per point increase) 0.93 0.86 to 1.01 0.01
Age (per 10 year increase) 0.81 0.62 to 1.06 0.17
Female proportion (per percentage point increase) 0.06 0.01 to 0.51 0.08
Treatment duration (per week increase) 1.03 0.89 to 1.2 0.26

The smaller 𝞽2 values for anxiety baseline and female proportion suggest that these predictors seem to explain the heterogeneity.

2.7 Secondary outcome: nausea

2.7.1 Pairwise meta-analysis

Figure 12 Forest plot for nausea for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.7.2 Risk of bias

Figure 13. Risk of bias assessment.

2.7.3 Meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity (𝞽2) observed in the effect sizes of the effect of pro-dopaminergic interventions on nausea.

OR 95% CI 𝞽2
Unadjusted effect 1.455 1.206 to 1.756 0.04
Moderator 95% CI 𝞽2
Age (per 10 year increase) 1 0.82 to 1.22 0.03
Female proportion (per percentage point increase) 1.11 0.2 to 6.09 0.03
Treatment duration (per week increase) 1.01 0.9 to 1.13 0.06

2.8 Secondary outcome: headache

2.8.1 Pairwise meta-analysis

Figure 14 Forest plot for headaches for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.8.2 Risk of bias

Figure 15. Risk of bias assessment.

2.8.3 Meta-regression analyses

The table below shows which of the covariates, if any, could modify the relative treatment effect of pro-dopaminergic interventions on headache. We did not perform a meta-regression on mean anhedonia and anxiety baseline scores as the total number of studies was below 10.

OR 95% CI 𝞽2
Unadjusted effect 1.14 1.019 to 1.275 0
Moderator 95% CI 𝞽2
Age (per 10 year increase) 0.95 0.84 to 1.08 0
Female proportion (per percentage point increase) 1.71 0.64 to 4.56 0
Treatment duration (per week increase) 1.01 0.94 to 1.07 0

2.9 Secondary outcome: insomnia

2.9.1 Pairwise meta-analysis

Figure 16 Forest plot for insomnia for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.9.2 Risk of bias

Figure 17. Risk of bias assessment.

2.9.3 Meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity (𝞽2) observed in the effect sizes of the effect of pro-dopaminergic interventions on insomnia.

OR 95% CI 𝞽2
Unadjusted effect 1.809 1.458 to 2.246 0.03
Moderator 95% CI 𝞽2
Age (per 10 year increase) 0.91 0.7 to 1.17 0.04
Female proportion (per percentage point increase) 0.83 0.13 to 5.2 0.04
Treatment duration (per week increase) 1.01 0.89 to 1.14 0.05

2.10 Secondary outcome: constipation

2.10.1 Pairwise meta-analysis

Figure 18 Forest plot for constipation for the comparison of pro-dopaminergic interventions vs placebo at 8 (4-12) weeks. OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.10.2 Risk of bias

Figure 19. Risk of bias assessment.

2.10.3 Meta-regression analyses

The table below shows which of the covariates, if any, could modify the relative treatment effect of pro-dopaminergic interventions on constipation.

OR 95% CI 𝞽2
Unadjusted effect 1.456 1.166 to 1.818 0
Moderator 95% CI 𝞽2
Age (per 10 year increase) 1.1 0.84 to 1.44 0.01
Female proportion (per percentage point increase) 0.42 0.07 to 2.6 0
Treatment duration (per week increase) 1.09 0.96 to 1.24 0.01

2.11 Secondary outcome: dizziness

2.12.1 Pairwise meta-analysis

Figure 20 Forest plot for dizziness for the comparison of pro-dopaminergic interventions vs placebo at 8 (4-12) weeks.

OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.11.2 Risk of bias

Figure 21. Risk of bias assessment.

2.11.3 Meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity (𝞽2) observed in the effect sizes of the effect of pro-dopaminergic interventions on dizziness.

OR 95% CI 𝞽2
Unadjusted effect 1.697 1.319 to 2.184 0.08
Moderator 95% CI 𝞽2
Age (per 10 year increase) 0.92 0.72 to 1.18 0.09
Female proportion (per percentage point increase) 0.18 0.03 to 1.29 0.06
Treatment duration (per week increase) 0.9 0.79 to 1.03 0.04

The smaller 𝞽2 values for female proportion and treatment duration suggest that these predictors may explain some of the heterogeneity.

2.12 Secondary outcome: dry mouth

2.12.1 Pairwise meta-analysis

Figure 22 Forest plot for dry mouth for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.12.2 Risk of bias

Figure 23. Risk of bias assessment.

2.12.3 Meta-regression analyses

The table below shows which of the covariates, if any, explain some of the heterogeneity (𝞽2) observed in the effect sizes of the effect of pro-dopaminergic interventions on dry mouth.

OR 95% CI 𝞽2
Unadjusted effect 2.134 1.731 to 2.631 0.05
Moderator \(\beta\) 95% CI 𝞽2
Age (per 10 year increase) 0.95 0.72 to 1.24 0.05
Female proportion (per percentage point increase) 0.14 0.03 to 0.76 0.02
Treatment duration (per week increase) 1.11 0.97 to 1.27 0.06

The smaller 𝞽2 value for female proportion suggests that this predictor seems to explain some of the heterogeneity.

2.13 Secondary outcome: vomiting

2.13.1 Pairwise meta-analysis

Figure 24 Forest plot for vomiting for the comparison of pro-dopaminergic interventions vs placebo at 4-12 weeks. OR: odds ratio, 95% CI: 95% confidence intervals. RIMA: Reversible inhibitors of monoamine oxidase-A, MAOI: monoamine oxidase inhibitors, DRI: dopamine reuptake inhibitor.

2.13.2 Risk of bias

Figure 25. Risk of bias assessment.

2.13.3 Meta-regression analyses

We did not perform any meta-regressions as the total number of studies was below 10.

2.14 Summary of evidence tables

Source of Evidence (Human studies)  Outcome   Timepoint  Summary of the association     Bias due to study limitations   Reporting bias   Indirectness     Bias due to other reasons  
Studies on pro-dopaminergic interventions vs placebo  Symptoms of anhedonia     6-10 weeks  N=6, n=2076;   SMD= -0.24,   95% CI: -0.46, -0.03 95% PrI: -0.77, 0.34  Moderate risk: 2 studies had high risk of bias, 2 had a moderate risk of bias. (Figure 3)  The impact of bias on the magnitude  e and direction of the effects of pro-dopaminergic interventions is unclear.    Low Risk   Moderate risk: 3 of the 6 studies used the Motivation and Energy Inventory, 2 used a single MADRS anhedonia item, and 1 used the IDS-IVR-30/IDS-C-30 Pleasure Scale. As anhedonia is a complex construct, “pleasure” scales and single items may fail at capturing the complexity of anhedonia in the context of depression.The impact of indirectness its direction is unclear.  No clear indication of other biases.  
Direct and indirect evidence for  pro-dopaminergic interventions (i.e., bupropion) vs placebo  Symptoms of anhedonia   (MADRS anhedonia item)  6-12 weeks  N=34, n=14054;   SMD= -0.12,   95% CI: -0.25 to 0.00  NA  NA    NA    NA 
Direct and indirect evidence for  non-dopaminergic interventions vs placebo  Symptoms of anhedonia   (MADRS anhedonia item)  6-12 weeks  N=34, n=14054;  SMD ranges from -0.05 (95% CI: -0.19 to 0.08) to –0.40 (95% CI: -0.48 to –0.32)    NA      NA      NA      NA   
Direct and indirect evidence of  pro-dopaminergic interventions (i.e. buproprion) vs non-dopaminergic   Symptoms of anhedonia   (MADRS anhedonia item)    6-12 weeks  N=34, n=14054;   SMD ranges from -0.28 (95% CI: -0.15 to 0.41) to -0.07 (95% CI: -0.23 to 0.09)    NA      NA      NA      NA   
Studies on   pro-dopaminergic interventions vs placebo  Anxiety   symptoms  4-12 weeks  N=11, n=3517; SMD=-0.17, 95%CI: -0.24, -0.09 95%PrI: -0.25, -0.08  Moderate risk: 73% of studies were rated as having an overall moderate risk of bias while 18% were rated as high risk of bias.    Low Risk      Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.  No clear indication of other biases.  
 Studies on pro-dopaminergic interventions vs placebo    Acceptability (dropout for any reason)  4-12 weeks  N=52, n=9725; OR=0.97,   95% CI: 0.79, 1.17 95% PrI: 0.37, 2.53  Moderate risk: 59% had a low overall risk of bias, 10% of studies were rated as having a high risk of bias, primarily due to concerns over outcome measurement, while 31% were rated moderate risk of bias.  Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.   Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.  No clear indication of other biases.  
 Studies on pro-dopaminergic interventions vs placebo    Tolerability   (dropout for side effects)  4-12 weeks  N=43, n=9030; OR=1.83,   95% CI: 1.38, 2.41 95% PrI: 0.67, 4.95  Low risk: 53% had an overall low risk of bias, 12% of studies had an overall high risk of bias, primarily due to concerns over outcome measurement, while 35% were rated moderate risk of bias.  Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.  Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.  No clear indication of other biases.  
 Studies on pro-dopaminergic interventions vs placebo    Constipation reported for pro-dopaminergic interventions vs placebo   4-10 weeks  N=21, n=5375; OR=1.46, 95% CI: 1.17, 1.82 95% PrI: 1.15, 1.84  Low risk: 77% of studies were rated as having an overall low risk of bias and 5% were rated high risk of bias.  Moderate risk:   The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.  Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.    No clear indication of other biases  
Studies on pro-dopaminergic interventions vs placebo    Dizziness reported for pro-dopaminergic interventions vs placebo   4-12 weeks  N=24, n=6026; OR=1.70, 95% CI: 1.32, 2.18 95% PrI: 0.89, 3.24  Low risk: 59% of studies were rated as having an overall low risk of bias and only 8% were rated high risk of bias.  Moderate risk:  The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.  Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.    No clear indication of other biases  
Studies on pro-dopaminergic interventions vs placebo    Dry mouth reported for pro-dopaminergic interventions vs placebo   4-10 weeks  N=26, n=6865; OR=2.13, 95%CI: 1.73, 2.63 95%PrI: 1.28, 3.56  Low risk: 67% of studies were rated low risk of bias for RoB2 while only 4% were rated high risk of bias.  Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.    Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.    No clear indication of other biases  
Studies on pro-dopaminergic interventions vs placebo    Headache reported for pro-dopaminergic interventions vs placebo   4-12 weeks  N=28, n=7084; OR=1.14, 95%CI: 1.02, 1.28 95%PrI: 1.00, 1.30  Low risk: 65% of studies were rated low risk for RoB2 while 31% were rated as moderate risk with scores of ‘some concerns’ spread out across domains in no clear pattern.  Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.     Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.  No clear indication of other biases  
Studies on pro-dopaminergic interventions vs placebo    Nausea reported for pro-dopaminergic interventions vs placebo   4-12 weeks  N=26, n=6489; OR=1.46,   95% CI: 1.21, 1.76  95% PrI: 0.92, 2.29  Low risk: 73% of studies were rated low risk for RoB2 while 23% were rated moderate.  Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.     Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.    No clear indication of other biases  
Studies on pro-dopaminergic interventions vs placebo    Insomnia reported for pro-dopaminergic interventions vs placebo   4-12 weeks  N=24, n=6432; OR=1.81,   95% CI: 1.46, 2.25  95% PrI: 1.18, 2.78  Low risk: 73% of studies were rated low risk for RoB2 while 23% were rated moderate.  Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.  Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.    No clear indication of other biases.  
Studies on pro-dopaminergic interventions vs placebo    Vomiting reported for pro-dopaminergic interventions vs placebo   6-12 weeks  N=5, n=962; OR=1.90, 95%CI: 0.90, 4.00 95%PrI: 0.82, 4.42  Moderate risk: 4of 5 studies were rated as moderate risk and 1 study as high risk due to concerns in RoB2 domains 3 (missing outcome data) and 4 (measuring the outcome).    Moderate risk: The potential for missing studies across the review was deemed to be low in domain 3 of the RoB-ME assessment however it was unclear whether some studies generated an eligible result.    Low risk: all studies included patients with depression receiving pro-dopaminergic interventions and assessed for anhedonia.  No clear indication of other biases.  

3. Abbreviations

4. Software Used

We used R version 4.3.1 (R Core Team 2023) and the following packages; meta (Balduzzi, Rucker, and Schwarzer, 2019); dplyr (Wickham et al. 2023); readxl (Wickham and Bryan, 2023); kableExtra (Zhu, 2024).

5. References

6 Table of included studies

Author (Year) Country Sponsor Treatment duration Intervention group Participants (n) Females (n) Age (mean) Dosage fixed or flexible Intervention format Planned dosage range (min-max mg/day) Delivered dosage range (min-max mg/day) Delivered dosage (mean mg/day)
Agosti (1991) USA NA 6 weeks Phenelzine 60-90mg 10 NA NA Flexible Oral 60mg to 90mg NA NA
Agosti (1991) USA NA 6 weeks Placebo 23 NA NA Flexible Oral NA NA NA
Agosti (1991) USA NA 6 weeks Selegiline 40mg 12 NA NA Fixed Oral 40mg 40mg NA
Amsterdam (1989) USA Sanofi Research (partial grant) 4 weeks Minaprine 100mg 34 12 41 Flexible Oral 100mg to 400mg NA 93mg
Amsterdam (1989) USA Sanofi Research (partial grant) 4 weeks Minaprine 200mg 39 25 37 Flexible Oral 100mg to 400mg NA 186mg
Amsterdam (1989) USA Sanofi Research (partial grant) 4 weeks Minaprine 300mg 43 22 40 Flexible Oral 100mg to 400mg NA 279mg
Amsterdam (1989) USA Sanofi Research (partial grant) 4 weeks Minaprine 400mg 37 22 37 Flexible Oral 100mg to 400mg NA 352mg
Amsterdam (1989) USA Sanofi Research (partial grant) 4 weeks Placebo 37 18 39 NA Oral NA NA NA
Amsterdam (2003) USA Somerset Pharmaceuticals, Inc.  8 weeks Selegiline 20mg 149 94 41.2 Fixed Transdermal 20mg 20mg NA
Amsterdam (2003) USA Somerset Pharmaceuticals, Inc.  8 weeks Placebo 152 99 43.5 Fixed Transdermal NA NA NA
Bakish (1992) Canada NA 6 weeks Moclobemide up to 600mg 58 26 42 Flexible Oral NA to 600mg NA to 600mg 492mg
Bakish (1992) Canada NA 6 weeks Placebo 56 20 44 Flexible Oral NA NA NA
Bellak (1966) USA *MH 4 weeks Placebo 25 NA NA NA NA NA NA NA
Bellak (1966) USA *MH 4 weeks Phenelzine 25 NA NA NA NA NA NA NA
Benes (2011) Germany GSK 12 weeks Placebo 67 45 59.5 Flexible to week 7, then fixed Oral NA NA NA
Benes (2011) Germany GSK 12 weeks Ropinirole 0.5-4mg 198 144 58.2 Flexible to week 7, then fixed Oral 0.5 mg to 4 mg NA 1.9 mg
Bodkin (2002) NA Somerset Pharmaceuticals 6 weeks Placebo 88 53 43.2 Fixed Transdermal NA NA NA
Bodkin (2002) NA Somerset Pharmaceuticals 6 weeks Selegiline 20mg 89 53 41.4 Fixed Transdermal 20mg 20mg 20mg
Botte (1992) NA NA 6 weeks Placebo 24 16 43.3 NA NA NA NA NA
Botte (1992) NA NA 6 weeks Moclobemide 300-600mg 23 13 51.4 Flexible Oral 300mg to 600mg 200mg to 600mg NA
Bymaster (2011) Romania, Serbia, USA DOV Pharmaceuticals, Euthymics Bioscience 6 weeks Placebo 29 19 49.5 Fixed Oral NA NA NA
Bymaster (2011) Romania, Serbia, USA DOV Pharmaceuticals, Euthymics Bioscience 6 weeks Amitifadine 50mg 34 25 48.2 Fixed Oral 50mg 50mg NA
Casacchia (1984) Italy NA 4 weeks Moclobemide 150-450 mg 18 8 49.5 Flexible Oral NA 150mg to 450mg 297.2mg
Casacchia (1984) Italy NA 4 weeks Placebo 16 11 49 Flexible Oral 150 to 400mg 150mg to 400mg 212.5mg
Chouinard (1993) Canada, UK NA 6 weeks Placebo 109 66 40.2 Fixed Oral NA NA NA
Chouinard (1993) Canada, UK NA 6 weeks Brofaromine 75-100mg 111 57 41.2 Fixed Oral 75mg to 150mg NA NA
Clayton (2006a) USA Glaxo Wellcome Inc.  8 weeks Bupropion 141 85 36.5 Flexible Oral 300mg to 450mg 300mg to 450mg 323mg
Clayton (2006a) USA Glaxo Wellcome Inc.  8 weeks Placebo 141 88 35.1 Flexible Oral NA NA NA
Clayton (2006b) USA Glaxo Wellcome Inc.  8 weeks Bupropion 138 76 37 Flexible Oral 300mg to 450mg 300mg to 450mg 309mg
Clayton (2006b) USA Glaxo Wellcome Inc.  9 weeks Placebo 137 76 37 Flexible Oral NA NA NA
Coleman (1999) USA Glaxo Wellcome Inc.  8 weeks Placebo 124 73 38.5 Flexible Oral NA NA NA
Coleman (1999) USA Glaxo Wellcome Inc.  8 weeks Bupropion SR 150-400mg 122 68 38.1 Flexible Oral 150mg to 400mg 100mg to 365mg 290mg
Coleman (1999) USA Glaxo Wellcome Inc.  8 weeks Placebo 152 92 36.7 Flexible Oral NA NA NA
Coleman (1999) USA Glaxo Wellcome Inc.  8 weeks Bupropion 150-400mg 150 95 36.6 Flexible Oral 150mg to 400mg NA NA
Corrigan (2000) USA NA 8 weeks Placebo 35 NA NA Fixed Oral NA NA NA
Corrigan (2000) USA NA 8 weeks Pramipexole 0.375mg 36 NA NA Fixed Oral 0.375mg 0.375mg 0.375mg
Corrigan (2000) USA NA 8 weeks Pramipexole 1mg 35 NA NA Fixed Oral 1mg 1mg 1mg
Corrigan (2000) USA NA 8 weeks Pramipexole 5mg 33 NA NA Fixed Oral 5mg 5mg 5mg
Croft (1999) NA Glaxo Wellcome Inc.  8 weeks Placebo 121 61 37.4 Flexible Oral NA NA NA
Croft (1999) NA Glaxo Wellcome Inc.  8 weeks Bupropion SR 150-400mg 120 61 35.9 Flexible Oral 150mg to 400mg 150mg to 400mg 293mg
Davidson (1988) NA Hoffmann La Roche 6 weeks Isocarboxazid 68 37 41.9 Flexible Oral NA NA 49.3mg
Davidson (1988) NA Hoffmann La Roche 6 weeks Placebo 62 35 41.9 Flexible Oral NA NA NA
DelBello (2014) USA Somerset Pharmaceutical, Inc.  12 weeks Placebo 156 104 14.7 Flexible Transdermal NA NA NA
DelBello (2014) USA Somerset Pharmaceutical, Inc.  12 weeks Selegiline 6-12mg 152 93 14.8 Flexible Transdermal 6mg to 12mg NA NA
Feiger (2006) USA Somerset Pharmaceutical, Inc.  8 weeks Selegiline 6-12mg 132 81 42 Flexible Transdermal 6mg to 12mg 6mg to 12mg NA
Feiger (2006) USA Somerset Pharmaceutical, Inc.  8 weeks Placebo 133 71 42 Flexible Transdermal NA NA NA
Feighner (1984) NA NA 4 weeks Placebo 22 19 49 NA Oral NA NA NA
Feighner (1984) NA NA 4 weeks Bupropion up to 600mg 44 30 43.9 Flexible Oral NA to 600mg 300mg to 600mg 392mg
Georgotas (1986) USA NAMH 7 weeks Placebo 28 15 64.7 Flexible Oral NA NA NA
Georgotas (1986) USA NAMH 7 weeks Phenelzine 22 13 65.5 Flexible Oral NA NA 53.90mg
Giller (1982) USA NAMH, Hoffman-LaRoche 6 weeks Placebo NA NA NA Flexible Oral NA NA 73mg
Giller (1982) USA NAMH, Hoffman-LaRoche 6 weeks Isocarboxazid NA NA NA Flexible Oral NA NA 48mg
GlaxoSmithKline (1980) USA GSK 6 weeks Bupropion 150-450mg 52 35 36.4 Flexible Oral 150mg to 450mg NA NA
GlaxoSmithKline (1980) USA GSK 6 weeks Bupropion 300-900mg 23 13 37.8 Flexible NA 300mg to 900mg NA NA
GlaxoSmithKline (1980) USA GSK 6 weeks Placebo 47 31 37.4 Flexible Oral NA NA NA
GlaxoSmithKline (1985) USA, Canada GSK 4 weeks Placebo 43 20 51.9 Fixed Oral NA NA NA
GlaxoSmithKline (1985) USA, Canada GSK 4 weeks Bupropion 300mg 45 18 52.4 Fixed Oral 300mg 300mg NA
GlaxoSmithKline (1985) USA, Canada GSK 4 weeks Bupropion 450mg 40 18 47.5 Fixed Oral 450mg 450mg NA
GlaxoSmithKline (1993) USA GSK 8 weeks Placebo 124 80 40.7 NA NA NA NA NA
GlaxoSmithKline (1993) USA GSK 8 weeks Bupropion SR 100mg 119 77 39.6 Fixed NA 100mg NA NA
GlaxoSmithKline (1993) USA GSK 8 weeks Bupropion SR 200mg 120 65 39.6 Fixed NA 200mg NA NA
GlaxoSmithKline (1993) USA GSK 8 weeks Bupropion SR 300mg 120 70 39.9 Fixed NA 300mg NA NA
GlaxoSmithKline (1993) USA GSK 8 weeks Bupropion SR 400mg 119 66 38.8 Fixed NA 400mg NA NA
GlaxoSmithKline (1994) USA GSK 8 weeks Bupropion 50-150mg 152 90 39.1 Flexible Oral 50mg to 150mg 50mg to 150mg NA
GlaxoSmithKline (1994) USA GSK 8 weeks Placebo 154 99 38.2 NA Oral NA NA NA
GlaxoSmithKline (1994) USA GSK 8 weeks Bupropion 100-300mg 150 98 37.2 Flexible Oral 100mg to 300mg 100mg to 300mg NA
Han (2012) South Korea Korea Research Foundation Grant 8 weeks Placebo 28 0 18.1 NA NA NA NA NA
Han (2012) South Korea Korea Research Foundation Grant 8 weeks Bupropion 150-300mg 29 0 21.2 Fixed Oral 150mg to 300mg NA NA
Hewett (2009) Austria, Belgium, Bulgaria, Croatia, Estonia, Finland, Greece, Ireland, Latvia, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden and Mexico GSK 8 weeks Placebo 199 142 41.8 Flexible Oral NA NA NA
Hewett (2009) Austria, Belgium, Bulgaria, Croatia, Estonia, Finland, Greece, Ireland, Latvia, Netherlands, Poland, Portugal, Russia, Slovakia, Spain, Sweden and Mexico GSK 8 weeks Bupropion XR 150-300mg 188 138 41.8 Flexible Oral 150mg to 300mg NA 170.1mg
Hewett (2010a) Australia, France, Germany, the Netherlands, Norway, South Africa and Sweden GSK 8 weeks Placebo 189 125 44.5 Flexible Oral NA NA NA
Hewett (2010a) Australia, France, Germany, the Netherlands, Norway, South Africa and Sweden GSK 8 weeks Bupropion XR 150-300mg 204 127 45.6 Flexible Oral 150mg to 300mg 150mg to 300mg 180mg
Hewett (2010b) Australia, Belgium, Canada, Croatia, Finland, France, Germany, India, Latvia, Netherlands, Norway, Poland, Republic of South Africa, Russia and United States GSK 10 weeks Placebo 207 144 71.3 Flexible Oral NA NA NA
Hewett (2010b) Australia, Belgium, Canada, Croatia, Finland, France, Germany, India, Latvia, Netherlands, Norway, Poland, Republic of South Africa, Russia and United States GSK 10 weeks Bupropion XR 150-300mg 211 157 70.9 Flexible Oral 150mg to 300mg 150mg to 300mg NA
Iosifescu (2022) USA Xsome Therapeutics 6 weeks Dextromethorphan + Bupropion 156 95 42.1 NA Oral 45mg to 105mg 45mg to 105mg NA
Iosifescu (2022) USA Xsome Therapeutics 6 weeks Placebo 162 117 41.2 NA Oral NA NA NA
Jarrett (1999) NA NA 10 weeks Phenelzine 0.85-1mg/kg 36 25 38.7 NA NA 0.85mg/kg to 1mg/kg NA 64mg
Jarrett (1999) NA NA 10 weeks Placebo 36 22 40.3 NA NA NA NA NA
Jefferson (2006) NA GSK 8 weeks Placebo 139 96 39.8 Flexible Oral NA NA NA
Jefferson (2006) NA GSK 8 weeks Bupropion XR 150-450mg 135 89 40 Flexible Oral 150mg to 450mg 150mg to 450mg NA
Koshino (2013) Japan, South Korea GSK 10 weeks Placebo 186 85 37.9 Fixed Oral NA NA NA
Koshino (2013) Japan, South Korea GSK 10 weeks Bupropion 150mg 190 92 36 Fixed Oral 150mg 150mg NA
Koshino (2013) Japan, South Korea GSK 10 weeks Bupropion 300mg 188 83 37.5 Fixed Oral 300mg 300mg NA
Kusalic (1993) NA NA 6 weeks Placebo 9 NA NA Flexible Oral NA NA NA
Kusalic (1993) NA NA 6 weeks Moclobemide 11 NA NA Flexible Oral NA NA 482.60mg
Larsen (1989) Denmark NA 6 weeks Placebo 18 12 57 Flexible Oral NA NA NA
Larsen (1989) Denmark NA 6 weeks Moclobemide up to 300mg 22 15 51 Flexible Oral NA to 300mg NA to 300mg NA
Learned (2012a) Australia, Belgium, Bulgaria, Canada, Estonia, Finland, France, Germany, India, Poland, Slovakia, and South Africa GSK 10 weeks Placebo 126 46 41.9 Fixed Oral NA NA NA
Learned (2012a) Australia, Belgium, Bulgaria, Canada, Estonia, Finland, France, Germany, India, Poland, Slovakia, and South Africa GSK 10 weeks GSK372475 1.5-2mg 134 51 43 Fixed Oral 1mg to 2mg 1mg to 2mg NA
Learned (2012b) Bulgaria, Canada, Chile, Costa Rica, Croatia, France, Germany, India, Italy, and Poland GSK 10 weeks Placebo 156 39 41.8 Fixed Oral NA NA NA
Learned (2012b) Bulgaria, Canada, Chile, Costa Rica, Croatia, France, Germany, India, Italy, and Poland GSK 10 weeks GSK372475 1-1.5mg 171 54 42.4 Fixed Oral 1mg to 1.5mg 1mg to 1.5mg NA
Liebowitz (1984) NA Public Health Service 6 weeks Placebo 24 14 37.7 Flexible Oral NA NA NA
Liebowitz (1984) NA Public Health Service 6 weeks Phenelzine 15-90mg 15 7 33.8 Flexible Oral 15mg to 90mg 60mg to 90mg 74mg
Mann (1989) USA Irma Hirschl and Mallinckrodt Foundations 6 weeks Placebo 22 17 40.2 Flexible NA NA NA NA
Mann (1989) USA Irma Hirschl and Mallinckrodt Foundations 6 weeks Selegiline up to 50mg 22 16 45.2 Flexible Oral NA NA to 50mg NA
Nair (1995) Canada, Denmark, UK NA 7 weeks Moclobemide 400mg 36 25 67 (median) Fixed Oral 400mg 400mg NA
Nair (1995) Canada, Denmark, UK NA 7 weeks Placebo 35 25 71 (median) Fixed Oral NA NA NA
Ose (1992) NA NA 4 weeks Moclobemide 300-500mg 35 21 49 (median) Fixed Oral 300mg to 500mg 300mg to 500mg NA
Ose (1992) NA NA 4 weeks Placebo 33 18 50 (median) Fixed Oral NA NA NA
Parnetti (1993) Italy Gruppo Sanofi 12 weeks Minapramine 200mg 63 36 71.6 Fixed Oral 200mg 200mg 200mg
Parnetti (1993) Italy Gruppo Sanofi 12 weeks Placebo 67 47 71.3 Fixed Oral NA NA NA
Quitkin (1990) USA *MH; NHCRC 6 weeks Phenelzine 90mg 33 NA 38.9 Fixed Oral 90mg 90mg NA
Quitkin (1990) USA *MH; NHCRC 6 weeks Placebo 34 NA 30.1 Fixed Oral NA NA NA
Raft (1981) USA *H 5 weeks Phenelzine 90mg NA NA NA Fixed Oral 90mg 90mg 90mg
Raft (1981) USA *H 5 weeks Placebo NA NA NA Fixed Oral NA NA NA
Rampello (1991) Italy NA 6 weeks Minaprine 100mg 10 NA NA Fixed Oral 100mg 100mh NA
Rampello (1991) Italy NA 6 weeks Placebo 10 NA NA Fixed Oral NA NA NA
Raskin (1972) USA *MH 5 weeks Placebo 111 NA NA Fixed Oral NA NA NA
Raskin (1972) USA *MH 5 weeks Phenelzine 45mg 110 72 37 (median) Fixed Oral 45mg 45mg NA
Ravaris (1976) NA Public Health Service; Warner Lambert Research Institute 6 weeks Phenelzine 60mg 21 NA 43.1 NA Oral 60mg 60mg NA
Ravaris (1976) NA Public Health Service; Warner Lambert Research Institute 6 weeks Phenelzine 30mg 21 NA 41.2 Fixed Oral 30mg 30mg NA
Ravaris (1976) NA Public Health Service; Warner Lambert Research Institute 6 weeks Placebo 21 NA 38.9 Fixed Oral NA NA NA
Reimherr (1998) USA Glaxo Wellcome Inc.  8 weeks Placebo 121 69 40.2 Fixed Oral NA NA NA
Reimherr (1998) USA Glaxo Wellcome Inc.  8 weeks Bupropion SR 150mg 121 86 38.3 Fixed Oral 150mg 150mg NA
Reimherr (1998) USA Glaxo Wellcome Inc.  8 weeks Bupropion SR 300mg 120 92 38.6 Fixed Oral 300mg 300mg NA
Rickels (1970) USA Public Health Service 4 weeks Methylphenidate 15mg NA NA NA Fixed Oral 15mg 15mg NA
Rickels (1970) USA Public Health Service 4 weeks Placebo NA NA NA Fixed Oral NA NA NA
Riesenberg (2010) USA Rexahn Pharmaceuticals 8 weeks Placebo 21 11 42.5 Fixed Oral NA NA NA
Riesenberg (2010) USA Rexahn Pharmaceuticals 8 weeks RX-10100 5mg 21 11 44.8 Fixed Oral 5mg 5mg NA
Riesenberg (2010) USA Rexahn Pharmaceuticals 8 weeks RX-10100 10mg 16 7 42.6 Fixed Oral 10mg 10mg NA
Riesenberg (2010) USA Rexahn Pharmaceuticals 8 weeks RX-10100 15mg 17 9 39.4 Fixed Oral 15mg 15mg NA
Robin (1958) UK NA 4 weeks Placebo 23 13 39.5 Flexible Oral NA NA NA
Robin (1958) UK NA 4 weeks Methylphenidate 20-40mg 22 16 37.5 Flexible Oral 20mg to 40mg NA NA
Rowan (1980) NA NA 6 weeks Phenelzine 45-75mg NA NA NA Flexible Oral 45mg to 75mg NA NA
Rowan (1980) NA NA 6 weeks Placebo NA NA NA Fixed Oral NA NA NA
Tomarken (2004) USA Glaxo Wellcome Inc.  6 weeks Bupropion SR 300-400mg 10 6 39.4 Fixed Oral 300mg to 400mg 100mg to 400mg NA
Tomarken (2004) USA Glaxo Wellcome Inc.  6 weeks Placebo 9 6 37.5 Fixed Oral NA NA NA
Ucha (1990) NA NA 6 weeks Placebo 24 13 42.2 Flexible Oral NA NA 5.6 tabs per day
Ucha (1990) NA NA 6 weeks Moclobemide 300-600mg 24 16 40.5 Flexible Oral 300mg to 600mg NA 405mg
UK Moclobomide Study Group (1994) UK NA 6 weeks Placebo 54 NA NA Fixed Oral NA NA NA
UK Moclobomide Study Group (1994) UK NA 6 weeks Moclobemide 450mg 56 NA NA Fixed Oral 450mg 450mg NA
Versiani (1989) NA NA 6 weeks Moclobemide 300-600mg 164 124 44 Flexible Oral 300mg to 600mg NA NA
Versiani (1989) NA NA 6 weeks Placebo 162 123 42 Flexible Oral NA NA NA
Versiani (1990) Brazil NA 6 weeks Moclobemide 600mg 25 NA NA NA Oral 600mg 600mg 600mg
Versiani (1990) Brazil NA 6 weeks Placebo 25 NA NA NA Oral NA NA NA
Versiani (1997) NA NA 6 weeks Moclobemide 75-750mg 108 73 41 Flexible Oral 75mg to 750mg 75mg to 750mg 633mg
Versiani (1997) NA NA 6 weeks Placebo 104 71 40 Flexible Oral NA NA NA
White (1984) USA NA 4 weeks Tranylcypromine 30-60mg 63 14 38 Flexible Oral 30mg to 60mg NA 44.4mg
White (1984) USA NA 4 weeks Placebo 59 21 39 Flexible Oral NA NA NA
Zarate (2006) NA NA 8 weeks Memantine 5-20mg 16 9 47.1 Flexible Oral 5mg to 20mg 5mg to 20mg 19.4mg
Zarate (2006) NA NA 8 weeks Placebo 16 7 46.1 Flexible Oral NA NA NA
Zisook (1985) NA NA 6 weeks Isocarboxazid up to 80mg NA NA NA Flexible Oral NA to 80mg NA 39.00mg
Zisook (1985) NA NA 6 weeks Placebo NA NA NA NA NA NA NA NA

7. Risk of Bias - Missing Evidence Assessment

7.1 ROB-ME Matrix Step 1

Meta-analysis Population Intervention Comparator Outome Eligible study designs: Eligible outcome definitions: Eligible methods of analysis:
Meta-analysis 1 Depressed adults Pro-dopaminergic intervention Placebo Anhedonia RCTs Anhedonia measured with any scale, up to 12 weeks post-randomisation Any method of analyses
Meta-analysis 2 Depressed adults Pro-dopaminergic intervention Placebo Anxiety RCTs Anxiety measured with any scale, up to 12 weeks post-randomisation Any method of analyses
Meta-analysis 3 Depressed adults Pro-dopaminergic intervention Placebo Acceptability RCTs Acceptability was measured by any dropouts occuring at any point in the treatment phase following randomisation Number of participants reporting event
Meta-analysis 4 Depressed adults Pro-dopaminergic intervention Placebo Constipation RCTs Constipation was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event
Meta-analysis 5 Depressed adults Pro-dopaminergic intervention Placebo Dizziness RCTs Dizziness was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event
Meta-analysis 6 Depressed adults Pro-dopaminergic intervention Placebo Dry mouth RCTs Dry mouth was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event
Meta-analysis 7 Depressed adults Pro-dopaminergic intervention Placebo Headache RCTs Headaches was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event
Meta-analysis 8 Depressed adults Pro-dopaminergic intervention Placebo Insomnia RCTs Insomnia was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event
Meta-analysis 9 Depressed adults Pro-dopaminergic intervention Placebo Nausea RCTs Nausea was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event
Meta-analysis 10 Depressed adults Pro-dopaminergic intervention Placebo Tolerability RCTs Tolerability was measured by any dropouts due to adverse events occuring at any point in the treatment phase following randomisation Number of participants reporting event
Meta-analysis 11 Depressed adults Pro-dopaminergic intervention Placebo Vomiting RCTs Vomiting was measured by any event of this occuring during the treatment phase following randomisation Number of participants reporting event

7.2 ROB-ME Matrix Step 2

1 = A study result is available for inclusion in the meta-analysis, 2 = no study result is available for inclusion in the meta-analysis, for a reason unrelated to the P value, magnitude or direction of the result, 3 = unclear whether an eligible study result was generated, 4 = no study result is available for inclusion in the meta-analysis, likely because of the P value, magnitude or direction of the result generated, . = study did not measure outcome based on information provided in the publication or clinical trial report.

Study ID Sources used Anhedonia (MA1) Anxiety (MA2) Acceptability (MA3) Constipation (MA4) Dizziness (MA5) Dry Mouth (MA6) Headache (MA7) Insomnia (MA8) Nausea (MA9) Tolerability (MA10) Vomiting (MA11)
UK Moclobomide Study Group (1994) Publication . . 3 1 3 1 3 3 3 1 3
Agosti (1991) Publication . . 3 3 3 3 3 3 3 3 3
Amsterdam (1989) Publication . . 1 3 3 3 3 3 3 3 3
Amsterdam (2003) Publication . . 1 3 1 1 1 3 1 1 3
Bakish (1992) Publication . . 1 3 3 3 3 3 3 1 3
Bellak (1966) Publication . . 1 3 3 3 3 3 3 3 3
Benes (2011) Publication . . 1 3 1 3 1 3 1 1 1
Bodkin (2002) Publication . . 1 3 1 1 1 1 3 1 3
Botte (1992) Publication . . 1 3 3 3 3 3 3 1 3
Bymaster (2011) Conference abstract, publication 1 . 1 3 3 3 1 1 1 1 3
Casacchia (1984) Publication . 1 1 3 3 3 1 3 3 3 .
Chouinard (1993) Publication . 1 1 1 1 1 1 1 1 1 3
Clayton (2006a) Publication, clinical result summary, clinical trial report . . 1 1 1 1 1 1 1 1 3
Clayton (2006b) Publication, clinical result summary, clinical trial report . . 1 1 1 1 1 1 1 1 3
Coleman (1999) Publication . . 1 3 3 1 1 3 1 1 3
Coleman (2001) Publication, clinical trial report . . 1 3 3 1 1 1 1 3 3
Corrigan (2000) Publication, clinical trial report . . 1 3 1 3 1 1 1 1 1
Croft (1999) Publication, clinical trial report . . 1 1 3 1 1 3 1 1 3
Davidson (1988) Publication . 1 1 3 3 3 3 3 3 1 3
DelBello (2014) Publication . . 1 3 1 3 1 1 1 1 1
Feiger (2006) Publication . . 1 3 1 1 3 1 3 1 3
Feighner (1984) Publication, clinical trial report . . 1 3 3 3 3 3 3 1 3
Georgotas (1986) Publication . . 1 1 1 1 3 3 3 1 3
Giller (1982) Publication . 1 3 3 3 3 3 3 3 3 3
GlaxoSmithKline (1980) Clinical trial report . 1 1 1 1 1 1 1 1 1 1
GlaxoSmithKline (1985) Clinical trial report . NA 1 1 3 1 1 1 1 1 1
GlaxoSmithKline (1993) Clinical trial report . 1 1 1 1 1 1 1 1 1 3
GlaxoSmithKline (1994) Clinical trial report . 1 1 1 1 1 1 1 1 1 3
Han (2012) Publication . . 1 3 3 3 3 3 3 1 3
Hewett (2009) Publication, clinical trial report 1 1 1 1 1 1 1 1 1 1 3
Hewett (2010a) Publication, clinical result summary, clinical trial report 1 1 1 1 1 1 1 1 1 1 3
Hewett (2010b) Publication, clinical trial report 1 1 1 1 1 1 1 1 1 1 3
Iosifescu (2022) Conference abstract, publication . . 1 3 1 1 1 1 1 1 3
Jarrett (1999) Conference abstract, publication, poster . . 1 3 3 3 3 3 3 1 3
Jefferson (2006) Publication, clinical trial report 1 1 1 1 1 1 1 1 1 1 3
Koshino (2013) Publication, clinical trial report 1 . 1 1 1 1 1 1 1 1 1
Kusalic (1993) Publication . . 3 3 3 3 3 3 3 3 3
Larsen (1989) Publication . . 1 3 1 3 3 3 3 1 3
Learned (2012a) Publication, clinical result summary . . 1 1 1 1 1 1 1 1 3
Learned (2012b) Publication, clinical result summary . . 1 1 1 1 1 1 1 1 3
Liebowitz (1984) Publication . 1 1 3 3 3 3 3 3 3 3
Mann (1989) Publication . . 1 1 1 1 1 1 1 3 3
Nair (1995) Publication . . 3 3 3 3 3 3 3 1 3
Ose (1992) Publication . . 1 3 3 3 1 1 3 1 3
Parnetti (1993) Publication . 1 1 3 3 1 3 3 1 . 3
Quitkin (1990) Publication . 1 1 3 3 3 3 3 3 1 3
Raft (1981) Publication . . 1 3 1 3 3 3 3 3 3
Rampello (1991) Publication . . 1 3 3 3 3 3 3 1 3
Raskin (1972) Publication . . 3 3 3 3 3 3 3 3 3
Ravaris (1976) Publication . 1 1 3 3 3 3 3 3 3 3
Reimherr (1988) Publication . 1 1 1 1 1 1 1 1 1 3
Rickels (1970) Publication . . 3 3 3 3 3 3 3 3 3
Riesenberg (2010) Conference abstract, publication . . 1 1 3 3 3 3 3 3 3
Robin (1958) Publication . . 1 3 3 3 3 3 3 1 3
Rowan (1980) Publication . . 3 3 3 3 3 3 3 3 3
Tomarken (2004) Publication . . 1 3 3 3 3 3 3 3 3
Ucha (1990) Publication . . 3 3 3 3 3 3 3 3 3
Versiani (1989) Publication . . 1 3 3 3 3 3 3 3 3
Versiani (1990) Publication . . 1 3 3 3 3 3 3 1 3
Versiani (1997) Publication . . 3 1 1 1 1 1 1 3 3
White (1984) Publication . . 1 1 1 1 1 1 3 3 3
Zarate (2006) Publication . . 1 3 3 3 3 3 3 1 3
Zisook (1985) Publication . . 3 3 3 3 3 3 3 3 3

7.3 ROB-ME Step 3 & 4

Scores indicate potential for missing studies in the review (3) and risk of bias due to missing evidence in the meta-analysis, as per the ROB-ME tool, abbreviations indicate answers to signalling questions in the tool algorithm N = no, PN = probably no, PY = probably yes, Y = yes, NA = question not applicable.

Outcome Specify meta-analysis Specify meta-analysis result Specify N Specify n 3.1 3.2 3.3 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Overall Risk of Bias Judgement
Anhedonia Random effects meta-analysis of the effect of dopamine agonists on symptoms of anhedonia at 4-12 weeks SMD -0.24 95%CI -0.46, -0.03 6 2079 N PY PY N NA N PY N NA NA NA L
Anxiety Random effects meta-analysis of the effect of dopamine agonists on symptoms of anxiety at 4-12 weeks SMD -0.17 95%CI -0.24, -0.09 16 3517 N PY PY N NA N PY N NA NA NA L
Acceptability Random effects meta-analysis of the effect of dropouts due to any reason OR 0.97 95%CI 0.79, 1.17 52 9725 N PY PY N NA Y PN N NA PN NA L
Constipation Random effects meta-analysis of reported constipation OR 1.46 95%CI 1.17, 1.82 21 5375 N PY PY N NA Y PY N NA PN NA SC
Dizziness Random effects meta-analysis of reported dizziness OR 1.70 95%CI 1.32, 2.18 24 6026 N PY PY N NA Y PY N NA PN NA SC
Dry mouth Random effects meta-analysis of reported dry mouth OR 2.13 95%CI 1.73, 2.63 26 6895 N PY PY N NA Y PY N NA PN NA SC
Headache Random effects meta-analysis of reported headache OR 1.14 95%CI 1.02, 1.28 28 7084 N PY PY N NA Y PY N NA PN NA SC
Insomnia Random effects meta-analysis of reported insomina OR 1.81 95%CI 1.46, 2.25 24 6432 N PY PY N NA Y PY N NA PN NA SC
Nausea Random effects meta-analysis of reported nausea OR 1.46 95%CI 1.21, 1.76 26 7046 N PY PY N NA Y PY N NA PN NA SC
Tolerability Random effects meta-analysis of dropouts due to adverse events OR 1.83 95%CI 1.38, 2.41 43 9030 N PY PY N NA Y PY N NA PN NA SC
Vomiting Random effects meta-analysis of reported vomiting OR 1.90 95%CI 1.13, 3.19 5 962 N PY PY N NA Y PY N NA PN NA SC